t-RNA synthetases are involved in protein biosynthesis so that inhibition thereof may be expected to lead to a cessation of cell growth. Thus, for instance, the compound mupirocin, produced by the organism Pseudomonas fluorescens, is an anti-bacterial agent and is used as the active ingredient in the product Bactroban, marketed by GlaxoSmithKline. Mupirocin has been shown to be an inhibitor of the isoleucyl t-RNA synthetase. Each t-RNA synthetase represents a separate target for drug discovery. t-RNA synthetase inhibitors which are selective for bacterial cells over mammalian cells are of considerable therapeutic interest as they have the potential to be used as anti-bacterial agents.
The sequence of the t-RNA synthetase genes in the Gram positive organism S aureus have recently been determined (see, for instance, European Patent application no 97300317.1, SmithKline Beecham, for S aureus MRS), thereby assisting the process of identifying inhibitors. In addition, the sequence of t-RNA synthetase genes in other pathogenic bacteria, for instance the Gram negative organism H influenzae, has also been published (R. D. Fleischmann et al., Science, 269, 496-512, 1995).
Lespagnol et al have described a group of 8-substituted theophylline derivatives, in particular 8-[2-(benzylamino)ethylamino]theophylline, which have hypotensive activity (Ann Pharm Fr, 1968, 26(3), 207-14).